IL-33 is a critical IL-1 family member that amplifies the responses of many cell types that are involved in asthma and atopic inflammation. IL-33 binds to Interleukin-1 Receptor-Like 1 (IL1RL1; also known as suppression of tumorigenicity 2 [ST2]), with high affinity and forms a ternary complex with IL1RAcP to form the signaling complex. This signaling complex leads to a series of events that is dependent on the Myddosome, with MyD88 and IRAK family members. This signaling ultimately leads to NFKb activation and other pathways in a cellular and cytokine environment specific context. When cells such as mast cells or basophils are stimulated by IL-33, type 2 cytokines such as IL-4, 5, and 13 are produced.
IL-33 has been shown to play a critical role in a number of preclinical models of asthma and allergic disease when its activity is blocked by either pharmacologic or genetic approaches. Blockade of the pathway has been accomplished by neutralizing antibodies to IL-33 or the receptor IL1RL1, genetic deletion of IL-33 or IL1RL1, or soluble forms of the receptor IL1RL1 coupled as a fusion protein to an Fc (Coyle et al., 1999, J. Exper. Med 190(7):895-902). In most model systems where physiologic allergens are used that contain a proteolytic allergen, such as in dust mite, cock roach or the fungus alternaria, IL-33 plays an important role in driving the inflammation and other aspects of airway remodeling (Chu et al., 2013, J. Allergy Clin. Immunol. 131:187-200). In pharmacologic models that rely on adjuvants for sensitization such as aluminum hydroxide (alum), or monosodium urate crystals, IL-33 plays an important role in the sensitization phase of the model and induction of type 2 cytokines such as IL-5 and IL13 (Hara et al., 2014, J. Immunol. 192(9):4032-4042). IL-33 has also been found to play an important role in the inflammatory response associated with viral infections in the airways. Damage of the airway epithelium by viral infections can trigger the release of IL-33 and modify the type of immune response.
Diseases such as chronic rhinosinusitis with nasal polyps (CRSwNP), atopic dermatitis (AD), and asthma are diseases where multiple cytokines are likely involved in the pathogenesis. The IL-33 receptor, ST2, is expressed on many of the cell types associated with type 2 inflammation, including mast cells, basophils, Th2-T cells, innate lymphoid cells type 2 and others (Cayrol & Girard, 2014, Current Opinion in Immunology 31:31-37; Molofsky et al. 2015, Immunity 42(6):1005-1019). The primary response of these cell types to IL-33 is the production of inflammatory cytokines, and in particular those associated with type 2 inflammation, including IL-5, IL-13, IL-4, IL-31 and IL-9 (Molofsky et al., 2015, Immunity 42(6):1005-1019; Rivellese et al, 2014, Eur. J. Immunol. 44(10):3045-3055; Suzukawa et al., 2008, J. Immunology 181(9):5981-5989; Vocca et al. Immunobiology 220(8):954-963; Maier et al., 2014, J. Immunology 193(2):645-654). Other cytokines as well as chemokines are also produced which are important in driving the recruitment of additional inflammatory cell types to the tissue site (Cayrol & Girard, 2014; Molofsky et al., 2015). The initial release of IL-33 is triggered by damage to the epithelium at the body or mucosal surfaces. Disease relevant triggers include allergens with proteolytic activity, physical damage to the epithelium, viruses as well as fungi and bacteria that are common at the body surfaces. In diseases where the tissue is rich with eosinophils and mast cells, damage to the epithelium sets off a cascade whereby IL-33 is released, acts on local target cells, and drives the production of multiple cytokines that are central to a Type 2 inflammatory response.